Ketogenic Diet to Improve Neuro-recovery

There is an urgent need for innovative therapies for improving neurorecovery after spinal cord injury (SCI). Despite extensive research, clinical advancements, and improved rehabilitation strategies, SCI continues to be a significant cause of disability and mortality. After a primary impact, the injured spinal cord undergoes multiple secondary pathological states that represent an important target in developing neuroprotective strategies for treatment of SCI. Even minor improvements in neurological recovery can have profound impacts on management of daily activities, secondary health complications, and quality of life. Thus, timely and effective strategies are of critical importance for positive outcomes after SCI. A number of pharmacological neuroprotective agents have been subject to intensive investigation in large, multicenter, prospective randomized controlled trials. Despite promising preclinical animal data, the primary outcomes of these clinical trials were largely negative. There is thus clear reason for researchers, clinicians, and patients to seek alternative therapies to enhance neurorecovery and functional status after SCI.

The scientific premise of this project rests upon accumulating evidence that diet-based therapies, such as the ketogenic diet (KD), offer effective neuroprotection against secondary injury cascades and improve forelimb motor function in a rat model of SCI and improve upper extremity motor function in patients with acute SCI. The KD is a high-fat, low-carbohydrate diet designed to mimic the metabolic and biochemical changes that occur during calorie restriction, specifically ketosis. Ketone bodies have been shown to exert neuroprotective effects by preventing oxidative damage; attenuating neuroinflammation and glutamate excitotoxicity; and inhibiting apoptosis in the brain and spinal cord. Because glutamate excitotoxicity, inflammation, and induction of apoptotic pathways lead to progressive degeneration in the spinal cord shortly after the injury, inhibition of these processes by ketone bodies may enhance neurological recovery after an SCI. In support of these hypotheses, we recently showed for the first time that, compared with a standard hospital diet (SD), 5 weeks of KD improved upper extremity motor function in patients with acute SCI. In addition, a neuroinflammatory blood protein, fibrinogen, was present at lower levels in the KD serum samples than in the SD serum samples. Taken together, our results suggest that a KD may induce anti-inflammatory effects in part by reducing fibrinogen, which promotes neuroprotection and improved recovery.

The acute stage post-SCI is also characterized by hyperglycemia, which is strongly associated with poor functional outcomes at discharge. These findings support the importance of achieving tight glycemic control in acute human SCI to obtain better neurological outcomes. Emerging evidence suggests that a KD can also improve the patient's metabolic state and maintain normal glycemic levels. In contrast, standard hospital diets have traditionally promoted a relatively high carbohydrate nutritional content. Consistent with previous findings, we have recently shown that 5 weeks of KD decreased fasting serum glucose levels by 24 mg/dl whereas levels increased by 0.7 mg/dl in the SD group. These provocative findings have led us to our central hypothesis that SCI patients who consume a KD over the first 5 weeks (average hospital stay) after injury will have better neurological recovery, functional independence, and glycemic control than the SCI patients who consume an SD during this period.